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Cells of multicellular organisms are in continuous conversation with the neighbouring cells. The sender cells signal the receiver cells to influence their behaviour in transport, metabolism, motility, division, and growth. How cells communicate with each other can be categorized by biochemical signalling processes, which can be characterised by the distance between the sender cell and the receiver cell. Existing classifications describe autocrine signals as those where the sender cell is identical to the receiver cell. Complementary to this scenario, paracrine signalling describes signalling between a sender cell and a different receiver cell. Finally, juxtacrine signalling describes the exchange of information between adjacent cells by direct cell contact, whereas endocrine signalling describes the exchange of information, e.g., by hormones between distant cells or even organs through the bloodstream. In the last two decades, however, an unexpected communication mechanism has been identified which uses cell protrusions to exchange chemical signals by direct contact over long distances. These signalling protrusions can deliver signals in both ways, from sender to receiver and vice versa. We are starting to understand the morphology and function of these signalling protrusions in many tissues and this accumulation of findings forces us to revise our view of contact-dependent cell communication. In this review, we will focus on the two main categories of signalling protrusions, cytonemes and tunnelling nanotubes. These signalling protrusions emerge as essential structural components of a vibrant communication network in the development and tissue homeostasis of any multicellular organism.

Paracrine Wnt/β-catenin signalling is important during developmental processes, tissue regeneration and stem cell regulation. Wnt proteins are morphogens, which form concentration gradients across responsive tissues. Little is known about the transport mechanism for these lipid-modified signalling proteins in vertebrates. Here we show that Wnt8a is transported on actin-based filopodia to contact responding cells and activate signalling during neural plate formation in zebrafish. Cdc42/N-Wasp regulates the formation of these Wnt-positive filopodia. Enhanced formation of filopodia increases the effective signalling range of Wnt by facilitating spreading. Consistently, reduction in filopodia leads to a restricted distribution of the ligand and a limited signalling range. Using a simulation, we provide evidence that such a short-range transport system for Wnt has a long-range signalling function. Indeed, we show that a filopodia-based transport system for Wnt8a controls anteroposterior patterning of the neural plate during vertebrate gastrulation. Distribution of Wnt morphogens in tissues is often graded, but it is unclear how these secreted factors move to form concentration gradients. Here, the authors show that Wnt8a is transported on actin-based filopodia, known also as cytonemes, that contact the signal-receiving cells during zebrafish gastrulation.

Signaling filopodia, termed cytonemes, are dynamic actin-based membrane structures that regulate the exchange of signaling molecules and their receptors within tissues. However, how cytoneme formation is regulated remains unclear. Here, we show that Wnt/planar cell polarity (PCP) autocrine signaling controls the emergence of cytonemes, and that cytonemes subsequently control paracrine Wnt/β-catenin signal activation. Upon binding of the Wnt family member Wnt8a, the receptor tyrosine kinase Ror2 becomes activated. Ror2/PCP signaling leads to the induction of cytonemes, which mediate the transport of Wnt8a to neighboring cells. In the Wnt-receiving cells, Wnt8a on cytonemes triggers Wnt/β-catenin-dependent gene transcription and proliferation. We show that cytoneme-based Wnt transport operates in diverse processes, including zebrafish development, murine intestinal crypt and human cancer organoids, demonstrating that Wnt transport by cytonemes and its control via the Ror2 pathway is highly conserved in vertebrates. Communication helps the cells that make up tissues and organs to work together as a team. One way that cells share information with each other as tissues grow and develop is by exchanging signaling proteins. These interact with receptors on the surface of other cells; this causes the cell to change how it behaves. The Wnt family of signaling proteins orchestrate organ development. Wnt proteins influence which types of cells develop, how fast they divide, and how and when they move. Relatively few cells, or small groups of cells, in developing tissues produce Wnt proteins, while larger groups nearby respond to the signals. We do not fully understand how Wnt proteins travel between cells, but recent work revealed an unexpected mechanism – cells seem to hand-deliver their messages. Finger-like structures called cytonemes grow out of the cell membrane and carry Wnt proteins to their destination. If the cytonemes do not form properly the target cells do not behave correctly, which can lead to severe tissue malformation. Mattes et al. have now investigated how cytonemes form using a combination of state-of-the-art genetic and high-resolution imaging techniques. In initial experiments involving zebrafish cells that were grown in the laboratory, Mattes et al. found that the Wnt proteins kick start their own transport; before they travel to their destination, they act on the cells that made them. A Wnt protein called Wnt8a activates the receptor Ror2 on the surface of the signal-producing cell. Ror2 then triggers signals inside the cell that begin the assembly of the cytonemes. The more Ror2 is activated, the more cytonemes the cell makes, and the more Wnt signals it can send out. This mechanism operates in various tissues: Ror2 also controls the cytoneme transport process in living zebrafish embryos, the mouse intestine and human stomach tumors. This knowledge will help researchers to develop new ways to control Wnt signaling, which could help to produce new treatments for diseases ranging from cancers (for example in the stomach and bowel) to degenerative diseases such as Alzheimer’s disease.

During embryogenesis, morphogens form a concentration gradient in responsive tissue, which is then translated into a spatial cellular pattern. The mechanisms by which morphogens spread through a tissue to establish such a morphogenetic field remain elusive. Here, we investigate by mutually complementary simulations and in vivo experiments how Wnt morphogen transport by cytonemes differs from typically assumed diffusion-based transport for patterning of highly dynamic tissue such as the neural plate in zebrafish. Stochasticity strongly influences fate acquisition at the single cell level and results in fluctuating boundaries between pattern regions. Stable patterning can be achieved by sorting through concentration dependent cell migration and apoptosis, independent of the morphogen transport mechanism. We show that Wnt transport by cytonemes achieves distinct Wnt thresholds for the brain primordia earlier compared with diffusion-based transport. We conclude that a cytoneme-mediated morphogen transport together with directed cell sorting is a potentially favored mechanism to establish morphogen gradients in rapidly expanding developmental systems.

π-Conjugated polymers that are electrochemically cycled in ionic liquids have enhanced lifetimes without failure (up to 1 million cycles) and fast cycle switching speeds (100 ms). We report results for electrochemical mechanical actuators, electrochromic windows, and numeric displays made from three types of π-conjugated polymers: polyaniline, polypyrrole, and polythiophene. Experiments were performed under ambient conditions, yet the polymers showed negligible loss in electroactivity. These performance advantages were obtained by using environmentally stable, room-temperature ionic liquids composed of 1-butyl-3-methyl imidazolium cations together with anions such as tetrafluoroborate or hexafluorophosphate.

Doc number: 12 Abstract Background: A fundamental requirement for development of diverse brain regions is the function of local organizers at morphological boundaries. These organizers are restricted groups of cells that secrete signaling molecules, which in turn regulate the fate of the adjacent neural tissue. The thalamus is located in the caudal diencephalon and is the central relay station between the sense organs and higher brain areas. The mid-diencephalic organizer (MDO ) orchestrates the development of the thalamus by releasing secreted signaling molecules such as Shh. Results: Here we show that canonical Wnt signaling in the caudal forebrain is required for the formation of the Shh-secreting MD organizer in zebrafish. Wnt signaling induces the MDO in a narrow time window of 4 hours - between 10 and 14 hours post fertilization. Loss of Wnt3 and Wnt3a prevents induction of the MDO , a phenotype also observed upon blockage of canonical Wnt signaling per se . Pharmaceutical activation of the canonical Wnt pathways in Wnt3/Wnt3a compound morphant embryos is able to restore the lack of the MDO . After blockage of Wnt signaling or knock-down of Wnt3/Wnt3a we find an increase of apoptotic cells specifically within the organizer primordium. Consistently, blockage of apoptosis restores the thalamus organizer MDO in Wnt deficient embryos. Conclusion: We have identified canonical Wnt signaling as a novel pathway, that is required for proper formation of the MDO and consequently for the development of the major relay station of the brain - the thalamus. We propose that Wnt ligands are necessary to maintain the primordial tissue of the organizer during somitogenesis by suppressing Tp53-mediated apoptosis.

Permeabilities for a series of gases through free-standing films of the conjugated polymer polyaniline are reported. A remarkable selectivity has been achieved for important gas pairs including hydrogen-nitrogen, oxygen-nitrogen, and carbon dioxide-methane. The selectivity values of 3590 for H$_2$/N$_2$, 30 for O$_2/N$_2$, and 336 for CO$_2$/CH$_4$ surpass the highest previously reported values of 313, 16, and 60 for the nonconjugated polymers poly(trifluorochloroethylene), cellulose nitrate, and a fluorinated polyimide, respectively. The process for tailoring gas selectivity of a polyaniline membrane involves first enhancing the permeabilities of gases with small diameters [<3.5 angstroms ($\\overset{\\circ}{\\mathrm A}$)] by doping and undoping the polymer film with counterions of an appropriate size. High selectivities are then achieved by decreasing the permeabilities of larger gases (> 3.5 $\\overset{\\circ}{\\mathrm A}$ diameter) through controlled redoping of the polymer. The permanent morphological changes induced in this conjugated polymer system and others indicate the potential for development of universal membranes for gas separatious.

The notochord defines the axial structure of all vertebrates during development. Notogenesis is a result of major cell reorganization in the mesoderm, the convergence and the extension of the axial cells. However, it is currently not fully understood how these processes act together in a coordinated way during notochord formation. The prechordal plate is an actively migrating cell population in the central mesoderm anterior to the trailing notochordal plate cells. We show that prechordal plate cells express Protocadherin 18a (Pcdh18a), a member of the cadherin superfamily. We find that Pcdh18a-mediated recycling of E-cadherin adhesion complexes transforms prechordal plate cells into a cohesive and fast migrating cell group. In turn, the prechordal plate cells subsequently instruct the trailing mesoderm. We simulated cell migration during early mesoderm formation using a lattice-based mathematical framework and predicted that the requirement for an anterior, local motile cell cluster could guide the intercalation and extension of the posterior, axial cells. Indeed, a grafting experiment validated the prediction and local Pcdh18a expression induced an ectopic prechordal plate-like cell group migrating towards the animal pole. Our findings indicate that the Pcdh18a is important for prechordal plate formation, which influences the trailing mesodermal cell sheet by orchestrating the morphogenesis of the notochord.

Lu et al report results for electrochemical mechanical actuators, electrochromic windows, and numeric displays made from three types of pi-conjugated polymers. Experiments were performed under ambient conditions, yet the polymers showed negligible loss in electroactivity.